This proposal is based on the central hypothesis that improved understanding of the molecular pathways that contributing to the disordered regulation of cell proliferation, differentiation, and apoptosis in T-cell lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) will ultimately lead to improved therapy of these diseases. The research will be accomplished through the coordinated efforts of 5 research projects and 2 cores. In Project 1, Tom Look will work closely with Rick Young to identify downstream target genes within TAL1-mediated transcriptional networks that contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in human T-cell malignancies. In Project 2, Harald von Boehmer will identify molecular pathways that cooperate with Notch1 signaling in lymphomagenesis by analyzing the impact of insertional mutagenesis, epigenetic regulation, and miRNA-dependent regulation on the generation of T-ALL from in Notch1 overexpressing T-cell progenitors. In Project 3, Peter Sicinski will study the molecular function of D-cyclins in Notch-driven murine T-ALL model (together with Harald von Boehmer) and in human T-ALL (with Tom Look). In Project 4, Fred Alt will elucidate molecular mechanisms and activated pathways associated with recurrent chromosomal translocations in thymic leukemias and lymphomas. In Project 5, Rick Young will identify the epigenetic mechanisms regulating normal T cell development and leukemogenesis and link them to the oncogenic action of TAL1 and Notch1 in T-ALL. Discoveries in murine models made by Drs. von Boehmer, Sicinski, Alt and Young will be immediately translated to determine relevance to human T-ALL/LBL molecular pathogenesis in collaboration with Dr. Look. These projects will be augmented with a Biostatistics Core (Donna Neuberg), to assist with the analysis of microarray data and the optimal design of animal experiments; and an Administrative Core (Tom Look and Harald von Boehmer), to oversee the administration and coordination of the research interactions among program investigators. Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole.